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PATHOLOGY OF

THE CARDIOVASCULAR SYSTEM Handout

Systemic Pathology II / VPM 2220

Shannon Martinson

Recommended Textbook: Miller LM and Gal A. Cardiovascular System and Lymphatic Vessel: In, Pathological Basis of Veterinary Disease, 6th Edition. Zachary Ed. Elsevier. 2017. Other references: Robinson WF and Robinson NA. Cardiovascular System: In, Jubb, Kennedy and Palmer's Pathology of Domestic Animals. Vol 3. 6th ed. Maxie, Ed. Elsevier. 2016.

Smith FWK Jr, Tilley LP, Oyama MA, Sleeper MM. Manual of canine and feline cardiology, 5th ed. Elsevier. 2016

Website: http://people.upei.ca/smartinson/

HEART STRUCTURE AND FUNCTION (for your information only) General considerations: The heart is the first organ to form in the embryo. In mammals and birds it consists of 4 chambers (2 atria and 2 ventricles). The heart functions to maintain adequate blood flow (cardiac output) with the purpose of delivering oxygen and nutrients to the tissues and the removal of waste metabolic products. The systemic circulation returns non-oxygenated blood to the right atrium via the venae cavae, passes to the right ventricle and from here is pumped to the lungs via the pulmonary arteries. The oxygenated blood returns to the left atrium via the pulmonary veins and finally the blood is pumped to the systemic circulation by the left ventricle. The heart is composed of three layers: pericardium (epicardium), myocardium (heart muscle) and endocardium. Pericardium and Epicardium: The pericardium is a double layered serosal membrane that covers the heart and the proximal part of the great vessels. These two serosal membranes are composed of thin mesothelium and connective tissue supporting blood and lymphatic vessels, nerves and adipose tissue. The epicardial fat generally follows the coronary grooves. The lymphatic vessels on the epicardial surface are occasionally prominent and can be mistaken for lesions. The pericardial space present between the epicardium and pericardium normally contains a small amount of clear lubricant fluid. Myocardium: The cardiac muscle is histologically similar but not identical to skeletal muscle. Myocardial fibres (cardiomyocytes) are striated, branched, and contain a nucleus in the centre of the fibre. They have characteristic intercalated disks through which fibres connect to each other allowing them to work as a single functional unit. The cytoplasm (sarcoplasm) contains myofilaments arranged in discrete bands (A, I, Z, bands), large numbers of mitochondria and abundant myoglobin. Purkinje fibers are special modified myocardial fibers responsible for impulse conduction. Connective tissue is present between cardiomyocytes.

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Endocardium: The inner lining of the heart and the valves are formed by endothelium (superficial), basal lamina and sub-endothelial connective tissue (elastic and collagen). The endocardium also holds part of the conductive system (Purkinje fibres). Valves: The heart has four valves that allow for unidirectional blood flow. These are the tricuspid valve (right AV valve); mitral valve (left AV valve or bicuspid valve); aortic valve; and pulmonary (pulmonic) valve. The normal valvular leaflets (cusps) are thin, smooth, and partially translucent. The valves are lined by the endocardium with an endothelium on the luminal surface. AV valves attach to the papillary muscles of the ventricular myocardium by the chordae tendineae. Post-mortem examination: There is no universal method to open the heart. The method chosen largely depends on the species, disease suspected and pathologist preference. The most important external features to be checked are: Cardiac Silhouette Shape Size Weight (total and ratios)

Color Pericardial fluid Fat deposits Coronary vessels

Wall thickness Valves Endocardium Great vessels

Once the heart has been opened, it is recommended to gently wash away excess blood from atria, ventricles and major blood vessels. Any abnormal change should be recorded and photographed for second opinion, if it is deemed necessary.

RESPONSE TO INJURY Important Consideration Regarding Cardiac Damage: Keep in mind that cardiomyocytes lose their ability to regenerate soon after birth – therefore healing following damage is limited. Fortunately, the functional reserve of the heart is reasonably good and compensatory mechanisms exist to mitigate damage. Cardiac disease, therefore does not necessarily progress to heart failure. When cardiac function is impaired, several physiologic mechanisms act to maintain cardiac output and tissue perfusion of vital organs. The most important mechanisms are: activation of neurohumoral systems, cardiac dilation and cardiac hypertrophy (eccentric cardiac hypertrophy and concentric cardiac hypertrophy).

NEUROHUMORAL ACTIVATION* Decreased cardiac output and the resulting decreased circulating blood volume lead to the release of norepinephrine by cardiac nerves causing increased heart rate, augmentation of cardiac contractility and increased vascular resistance (via vasoconstriction). There is also activation of the renin-angiotensin-aldosterone system, which results in increased reabsorption of sodium and water by the kidneys and vasoconstriction. The resulting expansion of the blood volume induces secretion of atrial natriuretic peptide; this enhances sodium and water excretion and induces vasodilation as a counter mechanism. Chronic activation of these systems ultimately leads to cardiovascular dysfunction.

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Preload refers to the

degree of muscle fiber

stretch just before

contraction (= volume of

blood in the ventricle just

prior to contraction)

Afterload refers to the

load against which the

myocardium exerts its

contractile force (= the

blood pressure the

ventricle must overcome

to eject blood)

PRELOAD AND AFTERLOAD

CARDIAC DILATION AND CARDIAC HYPERTROPHY* Overall enlargement of the heart is referred to as cardiomegaly. Cardiac dilation (Frank Starling Mechanism)* is a response to an increased workload (when more blood needs to pumped to meet the body’s demands) in both physiologic and pathologic states. In early cardiac dilation, the myocardial fibres stretch thereby increasing the contractile force, stroke volume and cardiac output (Frank-Starling relationship). Continued stretch increases contractile force, up to a limit, after which there is a decrease in tension developed. Various disease conditions can cause an increased preload and hence dilation of the heart, such as vascular shunts and valvular insufficiencies. Acute overload of a chamber is expected to lead to dilation, whereas chronic volume overload (chronic dilation) may lead to the development of eccentric cardiac hypertrophy (see below). Cardiac hypertrophy* can be primary or secondary to an increase in mechanical work or to trophic signals (as in hyperthyroidism in cats). Cardiac hypertrophy can be left ventricular, right ventricular, or bi-ventricular. Primary hypertrophy (ie cardiomyopathy) is less common, irreversible and most commonly seen in dogs and cats. Secondary hypertrophy is a physiologic and reversible increase in cardiac mass that results from an attempt to meet increased work demand. In pathologic states, hypertrophy is an adaptive response of limited benefit, where myocytes have impaired intrinsic contractility, impaired ventricular relaxation, and decreased compliance. This can cause increased end-diastolic pressure and ultimately lead to heart failure. Cardiac hypertrophy occurs in two distinct morphological types:

1. Concentric hypertrophy*: Increase in myocardial mass with thick ventricular walls and reduced ventricular chamber volume. This is usually associated with pressure overload. It occurs primarily via addition of sarcomeres in parallel to the long axes of the cells.

2. Eccentric hypertrophy*: Increase in myocardial mass with enlarged

ventricular chamber volume and relative thinning of the walls. This type of cardiac hypertrophy is accompanied by dilation and is usually associated with volume overload. It occurs primarily through addition of sarcomeres end-to-end, hence lengthening the cardiomyocytes.

Gross Changes in Cardiac Hypertrophy: Affected side Gross changes* Examples

Right side Heart broader at the base Pulmonary (arterial) stenosis, pulmonary hypertension (Cor Pulmonale)

Left side Increase heart length (axial) Sub-aortic stenosis, systemic hypertension, feline hyperthyroidism

Bi-ventricular Globose (rounded) shape Hypertrophic cardiomyopathy, various congenital heart defects e.g., tetralogy of Fallot

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Cardiac hypertrophy has three sequential cellular stages: 1. Initiation: increase in cell size by increasing the number of sarcomeres and

mitochondria. 2. Compensation: stable hyperfunction of the heart; absence or minimal clinical

signs of heart failure. 3. Deterioration: degeneration of hypertrophied cardiomyocytes, loss of

myocardial contractility and frank evidence of heart failure.

Myocardial Hypertrophy (Histopathology): Myocardial hypertrophy can be hard to evaluate microscopically without morphometric methods (measurement of cell size). Cardiomyocytes increase in width, nuclei increase in size, while sarcomeres, myofilaments and mitochondria increase in number. Hyperplasia (an increase in the number of cells) does not occur in heart muscle cells.

HEART FAILURE Heart failure occurs when the heart is unable to pump blood at a rate sufficient to meet the metabolic demands of the tissues. If cardiac dysfunction is not properly compensated, it eventually leads to heart failure and clinical signs. When the heart fails, it occurs because of an inability to adequately empty the venous reservoirs (“backward” or congestive heart failure) or, less commonly, as a result of decreased blood outflow via the aorta and/or pulmonic arteries (“forward” or low output heart failure). In the end-stage, these mechanisms can occur together. Signs of congestive heart failure include swollen abdomen (ascites), tachypnea and dyspnea (resulting from pleural effusion and pulmonary edema). The most common sign of low output heart failure is syncope and, may be accompanied lethargy, hypotension, cool extremities and weak pulses in the end-stage.

*Pathophysiologic patterns of heart disease

Disturbances in impulse formation/conduction

Depressed myocardial contractile strength

Impeded blood flow

Regurgitant blood flow

Abnormal pattern of blood flow (shunts)

Restricted atrial/ventricular filling

Clinically heart failure is divided into: Systolic Dysfunction Due to progressive deterioration of myocardial contractile function. Inability of the heart to pump blood forward.

Decreased myocardial contractility (myocardial damage and DCM)

Volume overload (valvular insufficiencies, L-R shunting)

Pressure overload (valvular stenosis)

Diastolic Dysfunction Due to inability of the heart chamber to expand and fill adequately during diastole.

Decreased ventricular relaxation or compliance (hypertrophic cardiomyopathy, restrictive cardiomyopathy)

Constrictive pericardial disease or cardiac tamponade

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CONGESTIVE HEART FAILURE*

Congestive heart failure occurs when diastolic filling pressures result in decreased venous outflow and increased venous and capillary hydrostatic pressure resulting in edema and congestion. It can be unilateral (left or right) or bilateral, and acute or chronic. Because the cardiovascular system forms a closed loop, failure of one side will ultimately cause failure of the other side. Fluid retention, edema, and venous congestion are typically observed.

Right heart failure* systemic venous and portal hypertension generalized edema and chronic passive congestion of the liver (nutmeg liver). Right heart failure may occur secondary to pulmonary hypertension (cor pulmonale)

o Horses and cattle: Hydrothorax, ascites, dependent edema, jugular distension

o Cats: Hydrothorax o Dogs: Ascites

Left heart failure* pulmonary venous congestion pulmonary congestion and edema (acute) intra-alveolar haemorrhage alveolar siderophages (=heart failure cells) and pulmonary fibrosis in chronic cases. Fluid accumulation in lungs caused by left heart failure is clinically referred to as cardiogenic pulmonary edema. Pulmonary edema causes dyspnea as the main presenting clinical sign.

CONGENITAL HEART AND BLOOD VESSEL DEFECTS Embryonic development of the heart and vasculature is complex and subject to many forms of malformations. In fetal circulation there are venous-arterial shunts in the atria, ventricles and great vessels (pulmonary artery and aorta). Atrial and ventricular communications close early in fetal life while the foramen ovale (atrial communication) and ductus arteriosus (pulmonic and aortic communication) close after birth. Some cardiac malformations are incompatible with intrauterine life resulting in embryonic resorption or fetal abortion; others can cause heart failure and clinical signs in postnatal life, while others are incidental (causing no clinical signs). The etiology of congenital heart defects is diverse including genetics (ie, gene/chromosomal abnormalities), maternal infections (eg, Parvovirus, Bluetongue virus, BVD virus), nutritional deficiencies (vitamin A, riboflavin), drugs (eg, thalidomide, ethanol, salicylates), and other teratogens (eg, radiation, fetal hypoxia, maternal diabetes). The cause may be multifactorial (ie, genetic and environmental factors). Often the cause is undetermined. There are many types and combinations of congenital heart or vessel diseases. They can be divided somewhat into categories based on the pathophysiology.

1. DEFECTS THAT CAUSE VOLUME OVERLOAD & ECCENTRIC HYPERTROPHY

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a. Left to Right shunts: When a defect is present between the right and left cardiac chambers, blood flows down the pressure gradient from the left to right side.

Patent Ductus Arteriosus (PDA)*: A common defect in all species, particularly dogs, in which females are affected 3x more often than males. The ductus arteriosus is a normal communication between the pulmonary artery and aorta in fetal circulation. This arterial communication normally closes functionally via smooth muscle contraction a few hours after birth (in foals occurs as late as ~ 5 days) and ultimately closes structurally forming the ligamentum arteriosum. In PDA, the ductus fails to close. Hemodynamics: blood shunts from the Aorta Pulmonary artery volume overload of the left ventricle (LV) and eccentric LV hypertrophy. In rare cases (with large defects), overcirculation of the lungs can result in pulmonary hypertension. If pulmonary hypertension is severe enough, right to left shunting (reversal) of the blood may occur leading to cyanosis (= Eisenmenger syndrome). Pressure overload of the right ventricle (RV) with concentric hypertrophy can occur under these circumstances.

Interatrial communications: Can occur due to 1) persistent foramen ovale or 2) a true defect in the closure of the atrial septum = atrial septal defect*. Atrial septal defects (ASD) may occur in all species but are most common in dogs and cattle. Atrial communication results in a L to R shunt and RV volume overload. Minor defects show no clinical signs. Hemodynamics: Large defect: Excessive blood flow from Left atrium (LA) Right atrium (RA) causing volume overload of the RV RV eccentric hypertrophy.

Ventricular Septal Defect (VSD)*: One of the most common cardiac defects in domestic animals (esp. horses, cattle) which is characterized by inter-ventricular communication in postnatal life. Embryologically, the interventricular septum is formed by upward growth of the muscular septum, downward growth of the conotruncal ridge, and the membranous septum, which is derived from the endocardial cushion. Defects in any of these 3 structures may result in a VSD. Relative to the position in the septum, VSD can be low (close to the apex - rare) or high (close to the AV valves - common). Hemodynamics: Blood flow from LV to RV Pressures between the 2 ventricles equalize and both sides hypertrophy (with the LV more obviously eccentric in nature). Clinically, left sided CHF is typical. With large defects, pulmonary hypertension can develop, and blood shunts could later reverse from RL causing cyanosis. This is called Eisenmenger complex when it occurs with VSD.

Predisposed breeds: Yorkshire terrier, Shetland sheepdog, Chihuahua, Poodle, Maltese terrier, Pomeranian, Newfoundland dog

Patent foramen ovale is not a true ASD – the valve is closed functionally by pressure differences between the atria.

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b. Valvular Regurgitation: Regurgitated blood from the ventricles to the atria leads to progressive atrial dilation and eccentric ventricular hypertrophy of the affected side.

Tricuspid Dysplasia*: (most common in cats and dogs; Labrador retrievers). Dysplastic valves are characterized by any combination of thickened fibrous leaflets, short or rolled leaflets, missing or abnormally short chordae tendineae, thick papillary muscles, and/or abnormal fusion of chordae or valve leaflets to the ventricular wall. Tricuspid dysplasia causes eccentric RV hypertrophy and R atrial enlargement.

Mitral Dysplasia* (left atrioventricular valvular insufficiency or stenosis): It is probably the most common congenital cardiac anomaly in cats; in dogs, it has been most commonly seen in English Bull Terriers, Mastiffs, Golden retrievers, and Great Danes. Anatomically, there can be any combination of an enlarged annulus, short thick leaflets, short thickened chordae tendineae, upward malposition of atrophic or hypertrophic papillary muscles, and enlargement of the left atrium and ventricle. Mitral valve dysplasia is often accompanied by tricuspid dysplasia, VSD or ASD. In Bull Terriers it may be accompanied by mitral stenosis

2. DEFECTS THAT CAUSE PRESSURE OVERLOAD AND CONCENTRIC

HYPERTROPHY Ventricular outflow obstruction causes a progressive /chronic increase in intraventricular pressure resulting in concentric hypertrophy of the affected side.

Pulmonic Stenosis*: (common in dogs; terrier breeds, beagles, English bulldogs). It is characterized by an abnormally reduced lumen in the pulmonic valve or adjacent region. Depending on the location, pulmonic stenosis is classified as valvular (most common), subvalvular (less common) or supravalvular (rare). The stenotic site is formed by fusion of the valve leaflets, a constricting band of fibrous or muscular tissue, or both. In some dogs (English bulldogs, boxers), an anomalous coronary artery obstructs the right outflow tract. Post-stenotic arterial dilation is generally found in the pulmonic artery, distal to

the stenotic site. Hemodynamics: Obstruction of right ventricular outflow → pressure overload of RV concentric RV hypertrophy post-stenotic dilation of the pulmonary artery if uncompensated, right heart failure.

Subaortic Stenosis*: (most common in pigs and dogs; Golden retrievers, Rottweilers, Bull terrier, Boxers, Newfoundlands). A nodule, crescent or complete ring of fibrous tissue narrows the left ventricular outflow tract below the aortic valve. Hemodynamics: Obstruction of the LV outflow LV pressure overload LV concentric hypertrophy post-stenotic dilation of aorta. If uncompensated, arrhythmias and syncope or sudden cardiac death can occur, especially during exertion; left heart failure and pulmonary congestion with edema are less common. Myocardial necrosis and fibrosis are not uncommon in affected dogs due to coronary lesions (intimal collagen proliferation). Dogs and

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pigs with subaortic stenosis may have concurrent mitral valve disease.

3. COMPLEXCONGENITAL HEART MALFORMATIONS In these diseases, nonoxygenated blood from the right heart compartments flows to the left heart compartments or directly into the systemic circulation. This also occurs in cases of PDA and VSD when there is reversal, resulting in R to L shunting.

Tetralogy of Fallot*: (cattle, dogs). Three congenital defects plus one acquired alteration: 1) Ventricular septal defect; 2) Pulmonic stenosis; 3) Dextroposition of the aorta (overriding aorta); 4) acquired Right ventricular hypertrophy. Hemodynamics: pulmonic stenosis RV overload RV hypertrophy. Increased RV pressure right to left blood shunt through the VSD venous blood enters systemic circulation cyanosis. Hypoxemia stimulates EPO release from the kidneys resulting in erythrocytosis. If uncompensated, severe cyanosis, severe hyperviscosity syndrome (due to erythrocytosis), or both may occur.

4. MISCELLANEOUS

Persistent Right Aortic Arch*: (most common in dogs). In PRAA, the aorta is incorrectly formed from right rather than from left 4rth aortic arch. The trachea and esophagus are enclosed by the abnormal aortic arch, pulmonary artery and the ligamentum arteriosum which results in localized esophageal constriction causing esophageal dysphagia, regurgitation and megaesophagus.

Ectopia cordis: (rare; mostly in cattle). The heart is located in an abnormal site. It may be extrathoracic, intraabdominal or pre-sternal. It is mostly found in stillborn animals or aborted fetuses, but rare animals may survive for a few days or weeks.

PATHOLOGY OF THE EPICARDIUM/PERICARDIUM

Serous atrophy of fat: Typically seen in severe emaciation and cachexia. The pericardial, visceral and bone marrow fat appear gelatinous. Pericardial Hemorrhages: These vascular changes are commonly seen during postmortem examination and, according to the size of the hemorrhage, are classified as petechial, ecchymotic or "paint brush" hemorrhages. Common causes of pericardial hemorrhages are septicemia, sepsis, toxemia, acute myocarditis, disseminated intravascular coagulation (DIC), and bleeding diatheses. Please note that pericardial hemorrhages are commonly seen in anoxic or in agonal states and these lesions should be interpreted accordingly Pericardial Effusions*: The significance of pericardial effusions largely depends on the rate of effusion rather than the volume. Given time, the overall size of the pericardium can progressively

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increase to accommodate the presence of fluid or exudate in the pericardial sac. Rapid filling of the pericardium, however, may not allow time for the pericardium to stretch. If intrapericardial pressure exceeds intracardiac pressure it can lead to compression of the heart preventing filling of the chambers during diastole resulting in decreased cardiac output and potentially heart failure (cardiac tamponade). In such cases, pericardiocentesis may need to be performed quickly to be life-saving.

Hydropericardium*: Accumulation of fluid (transudate) with low protein and low cellularity in the pericardial sac. The serosal surface remains smooth and glistening. Chronically the epicardium may become opaque, rough and thick. According to the pathogenesis, hydropericardium can occur as a result of:

Increased hydrostatic pressure: Right heart failure or pulmonary hypertension.

Decreased colloidal osmostic pressure (hypoproteinemia): Via loss of protein (protein losing enteropathy / nephropathy), decreased intake of protein (malnutrition / emaciation), decreased production of protein (liver disease).

Altered vascular permeability: Sepsis, disseminated intravascular coagulation (DIC), mulberry heart disease.

Decrease lymphatic drainage: Heart base or pericardial tumours.

Hemopericardium*: Accumulation of blood in pericardial sac. Common causes include: atrial rupture (may occur as a result of marked left atrial enlargement with severe mitral regurgitation), rupture of right atrial hemangiosarcoma in dogs, intra-pericardial aortic rupture (stallions), trauma, and iatrogenic (cardiac puncture). Accumulation of blood in the pericardium may cause cardiac tamponade and acute death. Caution: blood tinged fluid is frequently found as a post-mortem change in animals that have been dead for several hours.

Idiopathic hemorrhagic pericardial effusion has been reported in large/giant breed dogs and is indistinguishable clinically from other causes of hemopericardium when a mass lesion is not seen. The effusion may be hemorrhagic or serosanguineous.

Pericarditis*: Inflammation of the pericardium. Pericarditis tends to be diffuse involving both the pericardium and epicardium (epicarditis). The most common types of exudate are fibrinous and suppurative.

Suppurative pericarditis is most commonly seen in cattle as a complication of traumatic reticuloperitonitis (hardware disease).* Metal foreign bodies (wire, nails) may penetrate the reticulum and extend through the diaphragm into the pericardium and introduce bacteria from the reticulum. In cats

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suppurative pericarditis may accompany pyothorax and in dogs is can be seen with migrating grass awns.

Fibrinous pericarditis* typically results from hematogenous spread of bacteria to the pericardium.

o Common causes in ruminants: Mannheimia haemolytica, Clostridium chauvoei (Blackleg disease), E coli (septic calves), Streptococcus, Pasteurella multocida

o Common causes in pigs: Haemophilus parasuis (Glasser’s Disease)*, Streptococcus suis*, Mulberry heart disease* (usually scant fibrin and abundant fluid)

Chronic pericarditis generally leads to fibrosis and fibrous adhesions between the pericardium and epicardium, and between the pericardium and pleura. The formation of granulation tissue and fibrosis can result in constrictive pericarditis. The compressed heart may be smaller than normal or may be enlarged with concurrent ventricular hypertrophy (particularly when extra-pericardial adhesions are present). In constrictive pericarditis, the heart is encased in a dense fibrous scar that limits diastolic expansion and cardiac output potentially leading to right heart failure. The fibrous scar may obliterate the pericardial space or become calcified.

PATHOLOGY OF THE ENDOCARDIUM AND VALVES

Endocardial Hemorrhage: This is a very common finding on post-mortem examination. Endocardial hemorrhages occur in sepsis, toxemia, asphyxia, bleeding diatheses and as an agonal change. Endocardial Fibrosis and Fibroelastosis*:

Acquired localized endocardial fibrosis occurs in the so-called "jet lesions" caused by mechanical injury to the endocardium due to abnormal blood turbulence. Jet lesions are often seen in valvular insufficiencies and typically occur in the atria.

Acquired generalized endocardial fibrosis occurs whenever a ventricle or an atrium is dilated for a prolonged period. This is particularly prominent in dogs with dilated cardiomyopathy. When generalized, these lesions can impair and reduce stroke volume leading to congestive heart failure.

Grossly, the endocardium appears white, thick, and roughened.

Histologically, the endocardium is thickened by the abnormal deposition of collagen and elastic fibres.

Endocardial Mineralization*: Abnormal deposition of calcium or mineral in the endocardium and arteries (arterial medial calcification) occurs in all species. It can occur as a result of dystrophic or metastatic mineralization.

Possible causes include hypervitaminosis D (iatrogenic Vitamin D toxicity) or ingestion of Vitamin D analogs present in some rodenticides (calciferol) or toxic

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plants (Solanum malacoxylon and Cestrum diurnum).

Mineralization is also found in the endocardium of cachectic animals (i.e. tuberculosis, paratuberculosis) and in uremic dogs (uremic endocarditis).

Grossly, the endocardium is hardened and its surface is roughened due to the presence of pale yellowish plaques.

Valvular Cysts: These are common incidental findings, particularly in cattle. Cysts may be filled with clear yellow fluid (lymphocyst) or with blood (hematocyst). There are no associated clinical signs. Degenerative Heart Valve Disease (Myxomatous Valvular Degeneration or Valvular Endocardiosis):* The most common cardiac lesion in adult dogs. The incidence increases notably with age, for instance, in 1-year old dogs it is only 5% while in dogs older than 16 years, the incidence can reach 75%. Lesions are most common in toy, small and medium breed dogs and the disease is particularly prevalent in Cavalier King Charles spaniels. The cause is unknown but presumed to be genetic. Lesions most commonly involve the mitral valve, less commonly involve the tricuspid valve and rarely involve the aortic and pulmonary valves.

Grossly, affected valves are thickened and nodular but the surface remains smooth and glistening.

Histologically the lesion is characterized by nodular proliferation of fibroelastic tissue with increase mucinoid (myxoid) substance in the valve.

Mild myxomatous mitral valve degeneration is a common incidental finding at necropsy. More severe lesions can produce mitral valvular insufficiency, jet lesions, left atrial dilation, left ventricular eccentric hypertrophy and eventually left heart failure. In severe cases, rupture of chordae tendineae can cause valve prolapse and rapid death due to fulminant intractable pulmonary edema.

Endocarditis:* Inflammation of the endocardium is most frequently caused by bacteria and to a much lesser extent by fungi or parasites. According to location, endocarditis can be classified as valvular or mural (myocardial wall). It can be further classified as vegetative, in which a cauliflower-like mass of exudate and fibrin is attached to the valve or endocardium, or ulcerative when the endocardium is denuded. Typical clinical signs include pyrexia, lameness (from thromboemboli) and murmurs. Alterations to the valve may result in stenosis or insufficiency and subsequent congestive heart failure.

Valvular endocarditis is particularly common in farm animals suffering from bacteremia. Common causes include*:

Streptococcus equi and Actinobacillus equuli in horses

Trueperella pyogenes in cattle (most commonly involves right AV valve and follows hepatic abscessation and venal caval thrombosis )

Erysipelothrix rhusiopathiae and Streptococcus suis in pigs

Staphylococcus aureus, Streptococcus sp, and Bartonella in dogs

Bartonella and Streptococcus sp. in cats.

Congenital heart defects and the resultant "jet lesions” can predispose animals to bacterial endocarditis. In dogs, this is seen most often in the aortic valve in

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dogs with subaortic stenosis. Thromboembolism is a common sequel to vegetative endocarditis; mitral or aortic valve endocarditis causes renal infarcts while tricuspid and pulmonic lesions lead to pulmonary thromboemboli. Ulcerative mural endocarditis (with mineralization) is commonly seen in dogs with uremia.

PATHOLOGY OF THE MYOCARDIUM General response to myocardial injury Myocardial degeneration and necrosis*: The types of cellular degeneration and cellular necrosis of the cardiomyocytes are remarkably similar to those seen in skeletal muscle. Myocardial cells are particularly vulnerable to anoxia and injury caused by free radicals. Myocardial degeneration and necrosis may result in ventricular systolic or diastolic dysfunction (or both) causing heart failure. This occurs when lesions are extensive. Even when mild, these lesions can cause conduction disturbances (eg. AV node block or bundle branch block), if they are distributed along conduction pathways.

Gross appearance: if the number of affected fibres is considerable, the myocardium may appear pale (focal, multifocal, or diffuse).

Microscopically: myocardial degeneration and necrosis consists primarily of myofiber swelling, hypereosinophilia, loss of striation and dissolution of the sarcoplasm.

Myocardial calcification is a common sequel due to failure of Ca++ pump to extrude calcium from the sarcoplasmic reticulum.

Necrosis of cardiomyocytes is followed by leukocytic invasion and phagocytosis of sarcoplasmic debris by macrophages.

Unlike skeletal muscle, repair in myocardium is practically absent and therefore myocardial necrosis always results in myocardial fibrosis (scarring).

Myocardial degeneration and necrosis can be ischemic, toxic, nutritional or neurogenic: Ischemic Myocardial Necrosis: The classical heart attack which is so prevalent in humans is rarely seen in domestic animals, perhaps because coronary atherosclerosis is rare in animals (see atherosclerosis). Toxic Myocardial Necrosis*: The most common causes of toxic myocardial injury occur by ingestion of toxic plants such as white snakeroot (horses) or gossypol (pigs), cardiotoxic drugs such as doxorubicin, and ionophores such as monensin. Nutritional Myopathy*: White Muscle Disease (WMD). The myocardium is particularly vulnerable to free radical peroxidation, which occurs when there is a lack of adequate free radical scavengers. The occurrence of WMD is unpredictable and the theory of a geographic predisposition has been recently challenged. WMD is occasionally found in the neonate and fetus. The pathogenesis of WMD is related to the oxidation of cell membrane lipids (lipid peroxidation) by free radicals due to lack of oxygen radical-

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scavengers such as tocopherol (Vitamin E) and selenium containing enzymes (glutathione peroxidase / reductase). Membrane peroxidation induces a positive influx of Ca++ into the sarcoplasm and mitochondria. Since muscle activity relates to the production of free radicals, muscles with higher metabolic activity such as heart, diaphragm, intercostal muscles and tongue (predominantly type I fibers), are more severely affected. For unknown reasons, myocardial degeneration in WMD is typically on the left side of the bovine heart, while in ovine is on the right side. Neurogenic Myocardial Necrosis: Various types of CNS injury are known to cause myocardial degeneration (heart-brain syndrome). This syndrome is thought to be caused by the sudden release of catecholamines since endogenous (i.e., functional adrenal pheochromocytomas) and exogenous (injections) catecholamines can cause myocardial degeneration. INFLAMMATORY DISEASES OF MYOCARDIUM Myocarditis*: Inflammation of the myocardium rarely occurs alone and is more commonly part of systemic disease. According to the type of inflammatory infiltrate,

myocarditis can be classified as suppurative, lymphocytic, eosinophilic, haemorrhagic or granulomatous. Grossly the myocardium shows focal, multifocal or diffuse areas of pallor or discoloration. Some forms of myocarditis, such as lymphocytic myocarditis, can only be diagnosed microscopically. In some cases, suppurative myocarditis evolves into myocardial abscesses. Most forms of myocarditis are infectious or parasitic in origin. The most common forms:

Dogs – Canine parvovirus in young puppies*,Trypanosoma cruzi (Chaga’s disease)

Pigs - Encephalomyocarditis virus, Porcine circovirus-2 and Porcine Reproductive and Respiratory Syndrome (PRRS) virus as part of a systemic infection

Cattle - Histophilus somni* (vasculitis and papillary muscle infarction or multifocal abscesses) and Trueperella pyogenes*, Cysticerci in ruminants (Taenia sp).

Sheep – Staphylococcus aureus (“tick pyema”)

Apicomplexan parasites such as Toxoplasma gondii, Neospora caninum, Sarcocystis sp in many animal species.

CARDIOMYOPATHIES* The term “Cardiomyopathy” is used to describe cardiac diseases in which a primary myocardial abnormality results in changes in cardiac wall thickness (hypertrophy and/or dilation), electrical disturbances and possibly life-threatening decompensation in the form of congestive heart failure, or less commonly, sudden unexpected death. The underlying cause is genetic or idiopathic. It is often a diagnosis of exclusion, requiring us to rule out other causes of cardiac enlargement, such as cardiovascular shunts, valvular disease, and hypertension. NOTE: The term secondary cardiomyopathy is

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sometimes used for hypertrophy secondary to other primary conditions such as hyperthyroidism, taurine deficiency, etc. Cardiomyopathies are morphologically classified in multiple types:

i. Hypertrophic Cardiomyopathy (HCM)*: (cats > dogs). It is the most common type of feline heart disease, affecting~15% of the the entire feline population to some degree (mild and inconsequential in a substantial majority). Clinical signs may include lethargy, discomfort/hiding, dyspnea, tachypnea, acute paralysis of the hindlimbs, or in many cases, no overt signs at all but the auscultation of a heart murmur on routine examination (nonspecific finding). In cats, HCM may first appear as anesthetic death. Grossly, affected hearts show varying degrees of concentric hypertrophy (LV*, IVS +/- RV) and left atrial dilation. The hypertrophy may be symmetrical or asymmetrical in its distribution in the left ventricle but almost always affects the left ventricle more than the right. HCM is characterized by “stiff fibres” and impaired ventricular filling which leads to diastolic dysfunction. Microscopically there is myofibre disarray, hypertrophic cardiomyocytes and some fibrosis. Cats may have aortic "saddle" thrombi with concurrent posterior paresis and less often have atrial thrombi. Maine Coon and Ragdoll cats are predisposed with HCM in this breed resulting from a defect in the cardiac-myosin binding protein C3 gene (MyBPC3). Hyperthyroidism can result in similar gross and histologic changes in cats, although it typically results in uniform thickening of the left ventricle.

ii. Dilated or Congestive Cardiomyopathy (DCM)*: It is the most common type

of cardiomyopathy in dogs. In cats, secondary DCM historically was associated with dietary taurine deficiency; taurine deficiency also sporadically occurs in spaniel and retriever dogs, especially if fed a nutritionally imbalanced diet. DCM is mostly seen in large breed dogs (Doberman, Great Dane, Irish Wolfhound, Boxer) with strong familial tendencies, and sporadically in Holsteins. Typical clinical signs include depression, dyspnea, weight loss, syncope, murmurs, arrhythmias, or sudden death. There is bi-ventricular and atrial dilatation and the hearts show ventricular systolic dysfunction (reduced contractility) that can sometimes be very dramatic. The ventricular walls are thin and flabby. Microscopically there can be wavy attenuation, degeneration and loss of fibers with a variable degree of fibrosis; these changes are often subtle. Cats with DCM may have aortic thromboembolism.

iii. Restrictive Cardiomyopathy*: This cardiomyopathy is characterized by

impaired ventricular filling and diastolic dysfunction; it occurs primarily in cats. Murmurs and dysrhythmias are common. In this species, the disease has also been termed “left ventricular endocardial fibrosis” where endomyocarditis may be an antecedent condition. Grossly and microscopically there is diffuse endocardial thickening primarily involving the left ventricle and sometimes accompanied by mural thrombosis. Left atrial enlargement is often marked.

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iv. Arrhythmogenic right ventricular cardiomyopathy occurs primarily in Boxer dogs; rare cases have been reported in cats. In this cardiomyopathy, there is cardiomyocyte loss in the right ventricle with replacement by fibroadipose tissue. This process can trigger extensive and sometimes fatal disturbances in cardiac rhythm.

v. Other Primary Myocardial Abnormalities a. Excessive left ventricular moderator bands (false tendons) in the left

ventricle can bridge the ventricular septum and free wall entangling the papillary muscles. It appears to be a congenital defect that is only manifest later in life. These structures are often detected incidentally on echocardiography or on necropsy. In rare cases, they may be associated with left-sided heart failure in mature cats

b. Congenital endocardial fibroelastosis occurs as a hereditary disease Burmese cats. It is characterized by diffuse thickening of the endocardium accompanied by left ventricular hypertrophy and dilation in animals with no other cardiac abnormalities. Like restrictive cardiomyopathies, endocardial fibroelastosis impairs diastolic ventricular filling due to a noncompliant endocardium.

PATHOLOGY OF THE VASCULAR SYSTEM

General considerations: The vascular system is formed by arteries (elastic, muscular), arterioles, capillaries, venules and veins. Additionally, lymphatic vessels are considered part of the vascular system. The microcirculation is formed by arterioles, capillaries and venules and is where all exchanges between blood and tissue take place. The most important vascular diseases and lesions in domestic animals tend to affect arteries, arterioles and capillaries and to a lesser extent the veins and venules. Primary vascular lesions should be differentiated from secondary vascular changes. Vascular lesions may progress and cause partial or complete flow obstruction, ischemia, infarction and hemorrhage in affected organs. DEGENERATIVE ARTERIAL DISEASES Arteriosclerosis: It literally means “hardening of the arteries” and is more fully defined as chronic arterial change consisting of hardening, loss of elasticity and luminal narrowing resulting usually from proliferative and degenerative changes of the media and intima. In domestic animals, arteriosclerosis is common, but of little importance. The elastic arteries (abdominal aorta) are most frequently affected. Lesions are often localized around the orifices of arterial branches. The etiology/pathogenesis is not well defined, but the significant role of hemodynamic influences (turbulent blood flow) at arterial branching sites has been suggested. The lesions consist of slightly raised, firm, white plaques due to the accumulation of mucopolysaccharides, proliferation of smooth muscle cells in the tunica media, and fibrous tissue infiltration of the intima.

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Atherosclerosis and atheromas*: The term atherosclerosis is applied to lesions of arteriosclerosis in which degenerative fatty changes also occur. While perhaps one of the most important health problems in humans, atherosclerosis in animals is rare. Cholesterol plaques form in the arterial intima and media, particularly in the arteries of the heart, brain, mesentery and kidneys. Affected vessels are thickened, firm and yellow-white. Atheromatous plaques (atheromas) are composed of large foamy macrophages filled with lipid in the tunicas intima and media of the arterial wall. In animals, atherosclerosis is seen in:

Dogs with hypercholesterolemia associated with hypothyroidism, diabetes mellitus, and hyperlipoproteinemia (miniature schnauzers)

Pigs, rabbits and birds fed a high lipid diet

Aged psittacines (parrots) Arterial hypertrophy: The walls of medium size muscular arteries can thicken as the result of medial (smooth muscle) hypertrophy caused by sustained high blood pressure (hypertension) or increased volume flow. Medial hypertrophy of the arteries results in reduced elasticity and increased resistance.

Cats - Medial hypertrophy of the pulmonary arteries occurs commonly. It was speculated to be associated to Aelurostrongylus abstrusus or Dirofilaria immitis, however, identical lesions are found in specific pathogen free (SPF) cats.

Dogs - Medial hypertrophy is seen in the pulmonary arteries of dogs with Dirofilaria immitis and in the systemic arteries secondary to renal hypertension.

Cattle – Medial hypertrophy is seen in the pulmonary arteries in cattle raised at high altitudes (high altitude disease of cattle) due to hypoxia-induced pulmonary artery constriction. The resulting pulmonary hypertension ends in congestive right heart failure.

Aneurysm*: The word aneurysm refers to a localized weakening and dilation of blood vessels, particularly elastic arteries and to a lesser extent veins. There are two main anatomic types: i- Saccular aneurysm where there is a spherical dilation of the blood vessel resembling a balloon filled with blood; ii- Dissecting aneurysm in which a tear of the intima allows blood to enter into the potential space between the intima and media, progressively dissecting the wall of the vessel. Aneurysms are prone to rupture and cause hemothorax, hemoabdomen, hemopericardium, brain hemorrhage (stroke), etc. Spontaneous aortic rupture may occur in horses (stallions) and turkeys. The most common causes of aneurysms in animals include:

Strongylus vulgaris in horses (aorta, mesenteric)

Spirocerca lupi in dogs (aorta)

Copper deficiency in mares (uterine) and pigs.

Idiopathic in stallions and turkeys (dissecting aortic aneurysms with rupture) Arterial medial calcification: Occurs in conjunction with endocardial mineralization. Fibrinoid necrosis*: This is a unique but non-specific vascular change. The walls of affected arteries are necrotic and have deposits of acidophilic proteinaceous material (a mixture of fibrin, immunoglobulins, complement, and platelets). Fibrinoid change results

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from endothelial damage and occurs in many acute degenerative and inflammatory diseases of the small arteries and arterioles. These lesions are typically classified as necrotizing vasculitis. Causes include:

Nutritional deficiencies - Mulberry heart disease* (vitamin E / Selenium deficiency) in pigs. Characterized by fibrinoid necrosis and thrombosis of small vessels resulting in microhemorrhages and necrosis in the heart

Viral infections such as classical swine fever and malignant catarrhal fever

Bacterial toxins - Edema disease* of swine. In pigs, certain strains of hemolytic E. coli produce a cytotoxin that targets the vascular endothelium, resulting in fibrinoid necrosis of arterioles and resultant edema (eyelids, stomach, brain).

Immune mediated vasculitis - Purpura hemorrhagica* (in horses following infections with Streptococcus equi)

VASCULITIS (ARTERITIS AND PHLEBITIS)

Vasculitis: This is a general term that describes inflammation of a vessel (often small arteries and veins) which are detected mostly by histopathology. The consequences of vasculitis are grossly visible, and include hemorrhage, edema, thrombosis, and infarcts. Common causes of vasculitis include systemic infections (virus, bacteria, fungi), hypersensitivities where antigen-antibody complexes attached to the walls of blood vessels, and adverse drug reactions, among others. In many cases the blood vessel is just a bystander and the inflammatory response may result in thrombosis. Arteritis* refers to inflammation of the arteries. Important causes of arteritis include:

Strongylus vulgaris* – In horses. The 4rth larval stages migrate through the aorta and cranial mesenteric artery causing necrosis and inflammation of the intima (cranial mesenteric arteritis). In severe cases the vessel may be dilated and thick walled (fibrosis) with thrombosis. Larval worms can be observed in the thrombus. May cause colic. Collateral circulation makes infarction of the intestine uncommon. Adult worms reside in the intestinal lumen.

Dirofilaria immitis* – In dogs (less so cats). Adult worms reside in the pulmonary arteries and right ventricle. Inflammation in the arteries (proliferative endarteritis) causes pulmonary hypertension and may result in thromboembolism. Clinical signs reflect cardiovascular dysfunction and include cough and exercise intolerance, which may progress to congestive right heart failure. In cases with heavy worm burdens, worms may fill the right heart chambers and extend into the vena cava (vena caval syndrome) causing tricuspid regurgitation, hepatic congestion, ascites, shock (decreased venous return), hepatic/renal dysfunction and hemolysis.

Phlebitis: Inflammation of veins is rare in animals. Veins undergoing inflammation typically become thrombosed, hence the term thrombophlebitis. Pulmonary thromboembolism is a common sequela. The most common forms are:

Venal caval thrombosis* in cattle – occurs secondary to ruminitis and subsequent hepatic abscesses which can erode through the wall of the vena cava

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Femoral thrombophlebitis in “downer” cows – results from prolonged stasis

Omphalophlebitis* in neonatal farm animals from umbilical infections

Iatrogenic jugular phlebitis - caused by unsuccessful or repeated venipuncture or the use of indwelling catheters.

Other examples of diseases causing vasculitis (for your information only)

Viral Bacteria Fungi Parasites Toxins Immune mediated

Malignant catarrhal fever

Salmonella Mucor spp Angiostrongylus vasorum

Ergotism (fungus: Claviceps purpurea

Systemic lupus erythematosus

Bovine viral diarrhea

Histophilus somni

Aspergillus sp

Spirocerca lupi rheumatoid arthritis,

Classical and African Swine Fever

Erysipelothrix rhusiopathiae

Absidia Festuca spp/ mycotoxin Fusarium

Aleutian mink disease

Equine viral arteritis

Streptococcus spp

polyarteritis nodosa

Equine infectious anemia

Actinobacillus spp

Uremia

Bluetongue Disease

Feline infectious peritonitis

THROMBOSIS/ THROMBOEMBOLISM

Thrombosis and Thromboembolism*: Common sequel of vascular or endocardial diseases (endothelial damage) or bleeding diatheses. Causes include:

Horses: Strongylus vulgaris (mesenteric arteries)

Dogs: Dirofilaria immitis, Spirocerca lupi, nephrotic syndrome, IMHA, Cushing’s syndrome, pancreatitis, neoplasia

Cats: Primary cardiomyopathy, neoplasia

Cattle: Valvular endocarditis, venal caval thrombosis, septicemia, thrombotic meningoencephalitis (TME)

Pigs: Valvular endocarditis, septicemia, etc. LYMPHATIC VESSELS (for you information only) Congenital lymphatic diseases are rare except perhaps for hereditary lymphedema (inherited trait) seen sporadically in dogs, cats and pigs. Lymphedema results in aplasia or hypoplasia of lymphatic vessels causing severe subcutaneous edema particularly in the head, neck and limbs. Acquired lymphedema is caused by obstruction of lymphatic vessels most frequently associated to neoplasia, trauma or inflammation (lymphangitis).

DILATION AND RUPTURE OF LYMPHATIC VESSELS

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Lymphangiectasia: This term implies abnormal dilation of lymphatic vessels. Intestinal lymphangiectasia is a common cause of protein losing enteropathy in dogs and occurs less commonly in cats. Chylothorax and Chyloabdomen (chylous ascites). These two conditions result from the rupture of lymphatic vessels and leakage of chyle into the thoracic or abdominal cavities. Most cases are idiopathic and few others are caused by trauma, surgery (iatrogenic), inflammation (lymphangitis) or neoplasia. Chylous effusions obtained by thoracocentesis or abdominocentesis yield a white fluid resembling milk. Laboratory analysis typically shows a fluid rich in lymphocytes and triglycerides. LYMPHANGITIS Inflammation of the lymphatic vessels is called lymphangitis and may be seen with specific diseases such as:

Cattle: Johne’s disease (Mycobacterium paratuberculosis), tuberculosis (Mycobacterium spp)

Horses: Glanders (Burkholderia mallei), ulcerative lymphangitis (Corynebacterium paratuberculosis), epizootic lymphangitis (Histoplasma farciminosum), sporotrichosis (Sporothrix schenckii), among others.

NEOPLASTIC DISEASES OF THE CARDIOVASCULAR SYSTEM PRIMARY TUMOURS: Hemangioma*: Benign tumour of endothelial cells. Common in dogs, also found in cats, horses, sheep and pigs. This benign tumour can arise in any tissue but the skin is the most common site. Tumours are well circumscribed, red, blood filled masses. Histologically blood-filled vascular spaces are lined by a single layer of well differentiated endothelial cells. Hemangiosarcoma*: This is an important malignancy in veterinary patients but is less common than hemangioma. Hemangiosarcoma arises from endothelial cells and frequently metastasizes to other organs (or occurs multicentrically). It is most commonly seen in medium to large breed dogs (German shepherd, Golden retriever, Labrador retriever, Rottweiler) and the two most common primary sites in this species are spleen and right atrium; liver and lung are commonly involved. Grossly these tumours appear as single or multiple red hemorrhagic nodules. Microscopically, the neoplastic cells typically form blood channels lined by pleomorphic endothelial cells with high mitotic rate. Clinical signs are variable depending on the organs involved; splenic masses can rupture and cause hemoabdomen while atrial masses may rupture and cause rapid death due to cardiac tamponade. Anemia is also commonly found. Rhabdomyoma and Rhabdomyosarcoma of the heart: Rare neoplasia in domestic animals (most common in cattle); sometimes congenital. The tumour is grossly characterized by a well circumscribed white mass embedded in the heart muscle. The

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tumour often projects into the heart chambers. Aortic and Carotid Body Tumor or Chemodectomas (Non-chromaffin paraganglioma)*: Tumours of extra-cardiac tissues arising from chemoreceptors (aortic and carotid body) are rare and often are benign acting mainly as a space-occupying mass. Malignant tumours are often invasive and can produce metastasis. Aortic body tumours form single to multiple masses near the base of the heart inside the pericardial sac. They are slow-growing, non-resectable, and typically cause clinical signs due to pericardial effusion (cardiac tamponade) that is often slower to develop, and associated with a better long-term prognosis, than hemangiosarcoma. Carotid body tumours are firm white masses arising, in the neck near the bifurcation of the common carotid artery. In brachycephalic breeds, multicentric transformation of chemoreceptor tissue may occur resulting in concurrent aortic and carotid body tumours. Histologically, the tumors are formed by lobules of closely packed cuboidal or polyhedral neoplastic cells surrounded by thin connective tissue. (Ectopic thyroid tumours may produce heart base masses and are an important differential diagnosis) Mesothelioma: These malignant tumours can arise from the pericardium and may result in pericardial effusion (mesothelioma of the other body cavities may be present concurrently). The effusion may be a modified transudate or hemorrhagic. Pericardial mesothelioma tends to occur as a diffuse thickening of the pericardium rather than a distinct mass and can therefore be difficult to diagnose clinically, with the primary differential being idiopathic pericardial effusion. Repeated episodes of cardiac tamponade are typical and may occur weeks to months apart. Fluid analysis with cytology may be unrewarding as it is difficult to differentiate reactive and neoplastic mesothelial cells cytologically. Histopathology is required for confirmatory diagnosis. SECONDARY TUMORS: Many types of tumors can metastasize to the heart but the most frequent in domestic animals is by far lymphoma. Lymphoma*: This malignancy commonly involves the heart, producing multifocal to disseminated white nodules. Microscopically, affected myocardium is infiltrated by neoplastic lymphocytes. This is common in cattle with enzootic lymphoma. Histopathology is required for confirmatory diagnosis.